1. Field of the Invention
The present invention relates generally to methods for noninvasively measuring blood glucose or other analyte levels in a subject by measuring localized changes in light scattering from skin or other biological tissue. For example, such a method can include identifying tissue structures where the effect of blood glucose concentrations or levels are high, and targeting localized regions within the identified structures to measure blood glucose concentrations.
2. Description of the Related Art
Monitoring of blood glucose (blood sugar) levels has long been critical to the treatment of diabetes in humans. Current blood glucose monitors employ a chemical reaction between blood serum and a test strip, requiring an invasive extraction of blood via a lancet or pinprick to the finger. Although small handheld monitors have been developed to enable a patient to perform this procedure anywhere, at any time, the inconvenience associated with this procedure—specifically the blood extraction and the need for test strips—has led to a low level of compliance by diabetic patients. Such low compliance can lead to diabetic complications. Thus, a non-invasive method for monitoring blood glucose is needed.
Studies have shown that optical methods can be used to detect small changes in light scattering from biological tissue related to changes in levels of blood sugar. Although highly complex, a first order approximation of transmitting monochromatic light through biological tissue can be described by the following simplified equation:IR=I0 exp[−(μa+μs)L], where IR is the intensity of light reflected from the skin, I0 is the intensity of the light illuminating the skin, μa is the absorption coefficient of the skin at the specific wavelength of the light, μs is the scattering coefficient of the skin at the specific wavelength of the light, and L is the total path traversed by the light. From this relationship, it can be seen that the intensity of the reflected light decays exponentially as either the absorption or the scattering by the tissue increases. The attenuation of light can be characterized by an attenuation coefficient, which is the sum of μs and μa.
It is well established that there is a difference in the index of refraction between blood serum/interstitial fluid (IF) and cell membranes (such as membranes of blood cells and skin cells). (See, R. C. Weast, ed., CRC Handbook of Chemistry and Physics, 70th ed., (CRC Cleveland, Ohio 1989).) This difference can produce characteristic scattering of transmitted light. Glucose, in its varying forms, is a major constituent of blood and IF. The variation in glucose levels in either blood or IF changes the refractive index of blood-perfused tissue, and thus the characteristic of scattering from such tissue. Further, glucose-induced changes to the refractive index are substantially greater than changes induced by variation of concentrations of other osmolytes in physiologically relevant ranges. In the near-infrared (NIR) wavelength range, blood glucose changes the scattering coefficient, μs, more than it changes the absorption coefficient, μa. Thus, optical scattering of the blood/IF and cell combination varies as the blood glucose level changes. Accordingly, there is the potential for non-invasive measurement of blood glucose levels.
Current non-invasive optical techniques being explored for blood glucose applications include polarimetry, Raman spectroscopy, near-infrared absorption, scattering spectroscopy, photoacoustics, and optoacoustics. Despite significant efforts, these techniques have shortcomings, such as low sensitivity (signal-to-noise ratio) for the glucose concentrations at clinically-relevant levels, low accuracy (less than that of current invasive home monitors), and insufficient specificity of glucose level measurement within a relevant physiological range of 1.7-27.8 mM/L or 30-500 (mg/dL). For example, diffuse reflectance, or diffuse scattering, has been explored as a technique for noninvasively measuring levels of blood glucose. M. Kohl, Optics Letters, 19(24) 2170-72 (1994); J. S. Maier, et al., Optics Letters, 19(24) 2062-64 (1994). Using diffuse reflectance, a glucose-induced change of around 0.2%-0.3% in the scattering coefficient per 18 mg/dL (or 1 mM/L) has been measured. This measured change is too small to be utilized efficiently for a blood-glucose monitor for home use. Additionally, glucose-induced changes to the scattering coefficient can be masked by changes induced by temperature, hydration, and/or other osmolytes. Accordingly, there is a need for a method to conveniently, accurately, and non-invasively monitor glucose levels in blood.
Optical coherence tomography, or OCT, is an optical imaging technique that uses light waves to produce high-resolution imagery of biological tissue. OCT produces images by interferometrically scanning, in depth, a linear succession of spots and measuring absorption and/or scattering at different depths at each successive spot. The data then is processed to present an image of the linear cross section. The key benefits of such a system in imaging applications include the ability to achieve a high resolution, e.g., better than 10 micrometers, and the ability to select the depth at which a sample can be imaged. For example, blood vessels beneath the surface of the skin can be imaged using such a system.
As discussed in U.S. application Ser. No. 10/916,236, and in R. O. Esenaliev, et al., Optics Letters, 26(13) 992-94 (2001), the entire disclosure of which is incorporated by reference, it has been proposed that OCT might be useful in measuring blood glucose. However, difficulties associated with this technique include the large number of scans required to reduce optical noise, or speckle, which arises from wavefront distortion when coherent light scatters from tissue. While an OCT imaging system can reduce speckle by averaging it out over many scans or measurements, this approach is time-consuming, which makes the use of a conventional OCT imaging system impractical for in-home monitoring of blood glucose levels. Additionally, an OCT imaging system requires complex processing to form a workable image and to analyze the image data sufficiently in order to determine glucose levels.
Accordingly, there is a need for enhanced OCT systems for measuring analytes such as blood glucose levels.